1alpha,25-dihydroxy-vitamin-D3 as new immunotherapy in treatment of recurrent spontaneous abortion.

Recurrent spontaneous abortion (RSA) is serious health problem affecting 2-5% of reproducing couples worldwide. It has long been suspected that nearly 80% of the unexplained RSAs are due to immunologic causes. Although the major tissue confronting the mother's immune system is the placental villous trophoblast, the immunological risk to the developing embryo is not great until the time of implantation. In addition, trophoblast is not sensible to lysis by NK cells, TNF-alpha or macrophages, but may be killed by lymphokine activated NK cells (LAK) and may undergo apoptosis in response to TNF-alpha and/or IFN-gamma in vitro. The two most commonly used treatments for RSA are intravenous immunoglobulin (IVIg) and alloimmunization with partner's leukocytes (LIT). We promote vitamin D3 as new immunomodulatory agent in treatment of RSA. Different mechanisms have been proposed to account for the immunosuppressive effect of 1alpha, 25-dihydroxy-vitamin-D3 (VD3). Portion of the VD3 activity involves the downregulation of IL-2, IFN-gamma and TNF-alpha genes transcription. Because immunomodulatory effects of VD3 are very similar to IL-10 effects, acting of VD3 in immunotherapy of RSA syndrome, preeclamptic and eclamptic pregnancy, as well as PIH syndrome, is very reasonable. We propose using of VD3 as immunotherapy or adjuvant therapy in combination with classic immunotherapies of endangered pregnancies.

Failure of anti-tumor immunity in mammals--evolution of the hypothesis.

Observations on the morphological and functional similarity between embryonic or trophoblast tissues and tumors are very old. Over a period of time many investigators have created different hypotheses on the origin of cancerogenesis or tumor efficiency in relation to the host immune system. Some of these ideas have been rejected but many of them are still current. A presumption of the inefficiency of anti-tumor immunity in mammals due to the high similarity between trophoblast and embryonic cells to tumor cells is very real. The mechanisms for the escape of tumors from the immune response are very similar to the mechanisms for the escape of a fetoplacental unit from the maternal immune response. The similarity between these two mechanisms is so great that any randomness must be banished. At the same time, an incidence of malignant tumors and the types of more frequent tumors in non-mammalian vertebrates is significantly different to that in mammals. Lastly, the mechanisms of anti-tumor immunity in mammals are substantially different from the mechanisms of anti-tumor immunity in other classes of vertebrates. These facts indicate that the immune system of mammals during anti-tumor immune response is tricked by the similarity between tumor cells and trophoblast or other placental cells. From this aspect, our conclusion is that anti-tumor immunity failure in mammals can be defined as an immunoreproductive phenomenon, which is developed under the evolutionary pressure of autoimmunity and reproductive effectiveness.

Crossroads of extrathymic lymphocytes maturation pathways.

The majority of T cells located in peripheral lymphoid organs are dependents on the thymus for regular differentiation and function. Only a minority of T lymphocytes are thymus-independent. These cells pass by extrathymic maturation processes and become mature T lymphocytes. Some data suggest that mechanism of extrathymic lymphocytes maturation (eTLM) includes migration, proliferation, differentiation and selection of lymphocytes as well as thymic pathway. With aging and progression of thymic involution or in accidental thymic involution, pathway of eTLM derives emphasis. T cells from extrathymic pathway probably can polarize action of thymic-dependent T cells or participate in immune reaction in antigen-destructive or antigen-protective manners. Consequently, extrathymic pathways can be a source of self-reactive T cells or cells which participate in mechanisms of trophoblast or tumor escape. Results of eTLM probably are not presets, already depend upon many factors and microenvironmental snapshots. Factors like cytokines, prostaglandine, microbes, MHC molecules, hormones, Fas ligand, heat shock proteins, phenotypes of dendritic cells and APCs, probably can be polarizing courses of eTLM pathway. Definitive to the course of extrathymic-derived cells action, presumably is resultant of microenvironmental relations and interactions of foregoing factors. Hypothesis that microbes, especially viruses, can be promoters of extrathymic (self)antigen-reactive lymphocytes maturation is real as well as hypothesis that extrathymic lymphocytes selection and products of selected lymphocytes can be included in mechanisms of tumor, trophoblast and transplant rejection or escape.

Induction of thymic tolerance as possibility in prevention of recurrent spontaneous abortion.

A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive cells in the thymus and/or inhibition of specific Th(1) cells clones. Deletion process includes two selection mechanisms in which the thymus eliminates unwanted thymocytes are known as positive selection and negative selection. The thymus is an antigenically privileged site, mainly for it is discrete by blood-thymus barrier. Many researches were shown that intrathymic inoculation of any antigen resulted in specific tolerance induction. The embryo/fetus and placenta are an allograft to which the mother must remain immunologically tolerant in order for the fetus to survive. Today, there is much interest focused on the immunology of recurrent spontaneous abortion (RSA). Up to 50% of RSA may be mediated by the immune system via inadequate maternal anti-paternal response. Nature of this maternal-fetal disturbance represents disbalance in Th(1)/Th(2) activity. Contra-shift in Th(1)/Th(2) activity is the basis for immunotherapy with paternal leukocyte immunization (PLI). PLI induce some kind of peripheral tolerance on embryonic/fetal/trophoblast antigens, but problems of central tolerance are still open. Intrathymic inoculation of fetal or paternal cells (like leukocyte, thymic dendritic cells, trophoblast cells) or paternal set of MHC molecules may cause central specific tolerance and may be a new possibility for immunotherapy in RSA patients.

Origin of anti-tumor immunity failure in mammals and new possibility for immunotherapy.

There is now much evidence that tumors can be immunogenic. Tumor cells very often express antigens in a form recognizable by the host immune system, but most frequently without consequences on tumor progression. This has been shown in many experimental models and different experimental conditions. Immediate mechanisms for the escape of tumors from immune response are very similar with mechanisms for the escape of fetoplacental unit (as an allograft) from maternal immune response. Similarity between these two mechanisms is so significant that any randomness is banished. Mechanisms of anti-tumor immunity in mammals are substantially different in comparison with mechanisms of anti-tumor immunity in other classes of vertebrates. Moreover, type of most frequently tumors in non-mammalians vertebrates is also significant different. Incidence of malignant tumors in non-mammalians vertebrates is significantly less than incidence of malignant tumors in mammals. These facts indicate that immune system of mammals during anti-tumor immune response is tricked with similarity between tumor cells and trophoblast or other placental cells. It may be a specific evolutionary approach in rendering of anti-tumor immunity failure in mammals, and new possibility for anti-tumor immunotherapy.

Failure of blood-thymus barrier as a mechanism of tumor and trophoblast escape.

A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive clones in the thymus, but clonal deletion is not single mechanisms of thymic tolerance. There is now much evidence that intrathymic antigen expression results in anergy induction of T helper type-1 (Th1) clones in the periphery. Blood-thymus barrier is most important structure for prevention of unwanted penetration of antigens into the thymus. Impermeability of the barrier restrain induction of acquired thymic tolerance on unwanted antigens like microbes and tumor cells. Nevertheless, one of most important mechanism of tumor and trophoblast escape is in anergy of Th1 cells and in Th2 cells domination. Many mechanisms are included in disarrangement of Th1/Th2 balance in pregnancy and tumor bearers, but one of possibility is in failure of blood-thymus barrier. Possible consequences of blood-thymus barrier failure are trophoblast-specific or tumor-specific antigens penetrate into the thymus, deletion or anergy of antigen-specific clones and acquired thymic tolerance induction. Blood-thymus barrier is variable structure in anatomical and functional sense so that in certain condition foreign antigens probably can permeate across the barrier. Probability that some factors like hormones, cytokines, prostaglandine and neuromediators can affect blood-thymus barrier permeability and contribute in mechanisms of trophoblast and tumor escape is real but relatively unexplored.